Type II, non-insulin dependent, diabetes mellitus is characterized by endocrine abnormalities in pancreatic islets (insufficient insulin release) combined with enhanced glucagon release, as well as metabolic abnormalities in several target tissues of insulin (resistance to insulin's effects on glucose and lipid metabolism in muscle).
Current anti-diabetic therapies, such as sulfonylureas and insulin, partially correct the endocrine abnormalities associated with type II diabetes by either enhancing or supplementing the deficient, endogenous insulin secretion. These compounds have little, if any, ability to attenuate the associated insulin resistance in these individuals. Another structural class of compounds, thiazolidinediones, also has been demonstrated to lower blood glucose, insulin levels, and lipid levels in several animal models of type II diabetes. Because thiazolidinediones lower, rather than raise, insulin levels, they appear to have a different mechanism of action than either insulin or sulfonylureas and, thus, they have been termed insulin sensitivity enhancers (ISEs).
Unfortunately, thiazolidinedione ISEs also have been associated with weight gain, anemia, and cardiac hypertrophy. These unwanted side effects have slowed the development of thiazolidinedione ISEs for therapy for type II diabetes. The search for new classes of compounds that lower glucose, insulin and lipid levels via the same molecular mechanism as thiazolidinedione ISEs has been hampered by the fact that the molecular mechanism of thiazolidinedione ISEs remains unknown despite the numerous reports documenting that they have profound effects on glucose and/or lipid metabolism in liver, muscle and fat. Thus, the search for non-thiazolidinedione ISEs would greatly be facilitated by elucidation of a molecular mechanism for thiazolidinedione ISEs or by development of a screening procedure that could identify novel classes of compounds, which could trigger the same molecular mechanism as thiazolidinedione ISEs.